This is a competitive renewal grant application for an ongoing randomized, double blind, placebo-controlled clinical intervention study, the goal of which is to evaluate the chemopreventive activity of selenium against lung cancer in a population of asbestos exposed individuals. The proposed new experiments extend our current research aims and hypotheses into the areas of relevant genetic polymorphisms, IGF metabolism, and proteomics in order to explore and understand selenium's chemopreventive activity. The three aims of this work are: 1. Determine the extent to which responses in oxidative biomarkers to selenium supplementation are affected by polymorphisms in genes involved in antioxidant defense. In the current project, the effects of selenium supplementation on indicators of oxidative cellular damage in blood, urine, and the lung are being assessed. The goal of the work proposed in this new aim is to determine if levels of oxidative damage in asbestos exposed individuals differ based on polymorphisms in manganese superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPX) that have been associated with lung cancer risk, and assess whether the effects of selenium are modified by polymorphisms that occur in these genes. Lack of recognition of such effects could obscure the actual antioxidant activity of selenium supplementation; 2. Investigate the effect of selenium supplementation on IGF metabolism, and determine whether the response to selenium is modified by polymorphisms in genes involved in IGF metabolism. A growing number of reports hypothesize that IGF-1 and/or its primary binding protein, IGF-BP-3, are surrogate biomarkers for lung cancer risk, and some selenium compounds have been shown to alter circulating levels of IGF-1 consistent with a reduced risk for cancer. Initially, the effect of selenium on circulating levels of IGF-1 and IGF-BP-3 will be studied, and it will be determined whether polymorphisms in genes regulating IGF metabolism modulate the responses observed; and 3. Explore whether there exists a proteomic profile in serum and/or sputum that distinguishes among subjects with or without dysplasia of the bronchial epithelium, evaluate whether the proteomic profile is modulated by selenium supplementation, and determine what proteins comprise the proteomic profile. We propose studies using SELDI-TOF mass spectroscopy to identify a pattern of differential protein expression that reliably classifies individuals relative to the presence or absence of cytological dysplasia, and then determine if selenium supplementation modified the risk profile. Collectively, the proposed studies will not only provide greater understanding about the conditions under which selenium supplementation exerts its chemopreventive activity, but also will provide insights about the mechanism(s) by which selenium exerts its effects. In addition, this work has the potential to provide new biomarkers with which to assess lung cancer risk and its modulation. [unreadable] [unreadable]